Process for conversion of 3beta,17alpha-dihydroxy-5-pregnene-11,20-dione to cortisone acetate



S t Patent 2,883,403 BQGE FOR CONV SI N OF a v m DROXY-S-PREGNENE-11,20-DIONE T0 COR- TISONE ACETATE Edward S. Rothman, Philadelphia, and ,Monroe E. Wall, Oreland, Pa., assignbrs to the United States of America as represented by the secretarysofsAgricultnre Noni-swing. n pncarionlnareh 4, 1958 Serial-No. 719,170

'2 Claims. (or. 260--397.45)

(Granted under Title 35, US. 'Code (1952), see. 266) A non-exclusive, irrevocable, royalty-free license in the invention herein described, throughout the world for all purposes of the United States Government, with the power to grant sublicenses for such purposes, is hereby granted to the Government of the United States of America.

This invention relates to a process for converting 35, 17a-dihydroxy-5-pregnene-l1,20-dione to cortisone acetate or cortisone.

An object of the present invention is to provide a process for proceeding from 3B,17a-dihydroxy-5-pregnene- 11,20-dione to cortisone acetate which eliminates the Oppenauer oxidation and, more especially, the protective acetylation of the 17a-hydroxyl group. The latter reaction and the subsequent de-acetylation to l7a-hydroxyl cause an appreciable yield lowering at the final stages of cortisone manufacture where high yields are most significant. Furthermore, during all the final reactions of the process of this invention the C-21 function is an acetoxyl group, so it is not necessary to reacetylate the C-21 hydroxyl to obtain cortisone as its acetate, the usual product of commerce.

We have found that the desired A -3 keto moiety of cortisone can be obtained by oxidizing 2l-acetoxy-3fi,17adihydroxy-S-pregnene-l1,20-dione with chromic acid-sulfuric acid mixture in acetone medium. Not only is the dihydroxy acetone side chain stable under these conditions, but surprisingly, the undesirable rearrangements which often occur under acidic conditions did not take place. For example, undesired reactions such as fission of the entire easily-oxidizable dihydroxyacetone side chain, glycolic rearrangement of the l7a-hydroxyl group to the C-2l position to form a C-21 aldehyde group (known to occur when cortisone in methanolic hydrochloric acid is allowed to stand at room temperature) and D-homo rearrangement (D-ring expansion) did not occur.

The source material, 3/3,17a-dihydroxy-5-pregnene-1l, 20-dione, for the present process was prepared from 11- ketodiosgenin, as described in our copending application, Serial Number 644,184, filed March 5, 1957.

According to the present invention we brominate 3p, 17a-dihydroxy-5-pregnene-11,20-dione with two molecules of bromine thus to obtain 5,6,2l-tribromo-3 3,l7a-dihydroxyallopregnane-l1,20-dione. We then sequentially treat the product in acetone solution with sodium iodide and sodium or potassium acetate to obtain the new compound, 2l-acetoxy-3,B,17a-dihydroxy-5 pregnene ll,20- dione. Brief oxidation of this compound in acetone with chromic acid-sulfuric acid mixture gives a high yield of a new compound, isomeric with cortisone acetate, and differing from cortisone acetate only in the location of the double bond, viz. A instead of A. This new compound, 2l-acetoxy-l7a-hydroxy-5-pregnene-3,11,20-trione, is easily isomerized to 2'1-acetoxy-17a-hydroxy-4-pregnene-3,11,20-trione (cortisone acetate) by quite small (catalytic) amounts of acid or base, e.g. ammonia. The

-' improvements disclosed this invention l he 'clear' by the followingexamples.

'Example .l "Pre arazi n of .zzawerwt .aaira-ath ar' dwh I,

s .theCoursefif'l-QS hours; se-imelear bromineimdllifi'ii'tl. of carboii traehlo'ride wa'staddeii. this point "the entirequantity .6r. .sremia;as ,gpa'sied into sem'tion. Although attack at'C 2l seems to "go prererentially over addition at 5,6 we prefer to add a'second mole of bromine. It was sometimes necessary to add a little more chloroform in reactions where re-precipitation occurred or where turbidity developed. The second mole of bromine is taken up with some reluctance. At the end of the bromination solvents were removed in vacuo. The residue was dissolved in a liter of acetone and treated with 20 g. of sodium iodided with stirring at room temperature overnight. The steroids were isolated with ether and freed of iodine by very cautious treatment with a minimum of sodium thiosulfate solution. The solvents were again removed in vacuo and the steroids again dissolved in a liter of acetone containing 4 ml. of acetic acid and 20 g. of dry potassium acetate. The mixture was stirred at reflux for 12 hours and again steroidal matter w'asisolated with ether. The product was recrystallized from aqueous acetone to give needles dc-solvating at 97, and showing a double M.P. 112, 208-213", lai +33.0.

Example 2 Preparation of 2I-acetoxy-17u-hydroxy-5-pregnene-3, 11,20-trione.A sample of the preceding preparation, 1.35 g., was dissolved in 250 ml. of acetone (redistilled from potassium permanganate), cooled to 12 C. and treated with 1 ml. of an aqueous solution of 0.2672 g. chromium trioxide and 0.23 cc. of sulfuric acid. The reaction proceeded rapidly and within a minute a gray precipitate formed. After an additional two minutes passed, the reaction was stopped by dilution with 600 ml. of saline solution. The green solution gradually deposited a residue of pure white, flattened needles which were filtered off, washed with saline solution and with water. A sample was recrystallized from aqueous acetone to give pure 21- acetoxy-17a-hydroxy-5-pregnene 3,11,20 trione. The melting point depended somewhat on the rate of heating. Rapid determination on a preheated Kofler stage gave a value of ISO-183 C. A slower determination gave melting at 175 to a viscid mass that resolidified incompletely to short quadrangular forms reddening (decomposition) at 200 with final crystal disappearance at 220. The sample was nearly transparent to ultraviolet 239 mp radiation. E.=300 (methanol) without maximum. [a] =+44.3 (dioxane).

Example 3 Preparation of cortisone acetate-A sample of 350 mg. of 21-acetoxy-l7a-hydroxy-5-pregnene-3,11,20-trione was dissolved in 50 ml. of methanol and 0.4 ml. of concentrated ammonia water (28%) was added. The mixture was let stand minutes and the steroid was precipitated by addition of saline. The product after crystallization from aqueous methanol was cortisone acetate identical in every respect with authentic cortisone acetate.

Example 4 The isomerization was carried out identically with ample 3 except that the catalyst used was 0.4 ml. of 6 N HCl. The product was cortisone acetate.

"1'."A"piocess"for'converting 3,8,17a dihydroxy 5-pregnene-11,20-dione to cortisone acetate comprising brominetting ,318,1T/pudihydroxymregnene-1.1,-20- dione to obtain "SIGQZHribtnib-Sp,17a-clihydroxyallopregnane-11,20 dione, reacting the latter successively with sodium iodide and a reagent consisting ofacetic acid and a salt sestand in a medium selected from the group consisting of a basic alcoholic solution and an acidic alcoholic solution to isomerize 2l-acetoxy-17u-hydroxy-5-pregnene-3,11,20- trione to 21-acctoxy-17a-hydroxy 4 pregnene 3,11,20- trione. v

2.; 2l-acetoxy-17a-hydroxy-5-pregnene-3,1 1,20-trione.

References Cited in the file of this patent v UNITED STATES PATENTS 2,668,816- Miescher etal. Feb. 9, 1954 2,786,856 Cutler et a1 Mar. 26, 1957 2,787,623' Gebert Apr. 2, 1957 2,805,230 Stork et a1 Sept. 3, 1957 

1. A PROCESS FOR CONVERTING 3B,17A DIHYDROXY-5-PREG-ENE NENE-11,20-DIONE TO CORTISONE ACETATE COMPRISING BROMINATING 3B,17A-DIHYDROXY-5-PREGNENE-11,20-DIONE TO OBTAIN 5,6,21-TRIBROMO-3B,17A-DIHYDROXYALLOPREGNANE-11,20 - DIONE, REACTING THE LATTER SUCCESSIVELY WITH SODIUM IODIDE AND A REAGENT CONSISTING OF ACETIC ACID AND A SALT SELECTED FROM THE GROUP CONSISTING OF POTASSIUM ACETATE AND SODIUM ACETATE, AND RECOVERING 21-ACETOXY-3B,17A-DIYDROXY HYDROXY-5-PREGNENE-11,20-DIONE, ADDING CHROMIUM TRIOXIDE-SULFRIC ACID MIXTURE TO A COLD ACETONE SOLUTION OF THE 21-ACETOXY-3B,17A-DIHYDROXY-5-PREGNENE-11,20-DIONE TO OXIDIZE THE 3B-HYDROXY FUNCTION, RECOVERY 21-ACETOXY17A-HYDROXY-5-PREGNENE-3,11,20-TRIONE AND ALLOWING IT TO STAND IN A MEDIUM SELECTED FROM THE GROUP CONSISTING OF A BASIC ALCOHOLIC SOLUTION AND AN ACIDIC ALCOHOLIC SOLUTION TO ISOMERIZE 21-ACETOXY-17A-HYDROXY-5-PREGNENE-3,11,20TRIONE TO 21-ACETOXY-17A-HYDROXY-5-PREGNENE,3,11,20TRIONE.
 2. 21-ACETOXY-17A-HYDROXY-5-PREGNENE-3,11,20-TRIONE. 